The link between aggregated amyloid (A?) to downstream events, including hyperphosphorylated tau and synaptic loss and cognitive decline in Alzheimer's disease (AD) remain to be elucidated. Growing lines of evidence suggests that astrocyte dysfunction may contribute to the development and progression of AD. Specifically, astrocytic glutamate transporter (GLT-1) decrease has been shown in AD. I want to elucidate the role of GLT-1 dysfunction in the progression or initiation of AD pathology. First, I will generate two suitable in vivo transgenic mouse models: one overexpressing human wildtype tau (hTau) with a conditional knockout out of GLT-1 in the forebrain region (NST-GLT1-KO) and the other expressing A? (J20) with NST-GLT1-KO. Second, I will conduct temporal assessment on cortical-dependent and hippocampal-dependent cognition by novel object recognition and novel object in place tests respectively. Third, I will compare temporal changes of A? pathology in J20-NST-GLT1-KO and tau pathology in hTau-NST-GLT1- KO mice. I will also compare the pathologies between the single and double transgenic mice. Finally, I will assess synaptic and dendritic changes by Golgi staining and immunofluorescence staining. These steps will determine whether the loss of the glutamate transporter activity is sufficient to 1) trigger a buildup of tau, synaptic loss and cognitive decline in human tau overexpressing mice and 2) exacerbate A? pathology. Hypothesis: Functional loss of GLT-1 triggers and exacerbates A? buildup and tau pathology, resulting in synaptic loss and cognitive decline. Aim 1: Determine whether the functional loss of GLT-1 triggers tau pathology, synaptic loss and cognitive decline in a mouse model of AD. Aim 2: Determine whether the functional loss of GLT-1 triggers aberrant neuronal excitatory activity and exacerbates A? pathology in a mouse model of AD. The contribution of this research includes a better understanding on the role of astrocyte dysfunction in the early stages of AD and its consequences on the progression of the disease. The data from this research proposal will elucidate potential therapeutic targets in the early stages of AD and tau-related neurodegenerative disease (tauopathies).